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Methylnaltrexone inhibits opiate and VEGF-induced angiogenesis: role of receptor transactivation
P A Singleton1, M W Lingen, M J Fekete
1Department of Medicine, University of Chicago, Chicago, IL 60637, USA.
Abstract:
Angiogenesis or the formation of new blood vessels is important in the growth and metastatic potential of various cancers. Therefore, agents that inhibit angiogenesis have important therapeutic implications in numerous malignancies. We examined the effects of methylnaltrexone (MNTX), a peripheral mu opioid receptor antagonist, on agonist-induced human EC proliferation and migration, two key components in angiogenesis. Using human dermal microvascular EC, we observed that morphine sulfate (MS), the active metabolite, morphine-6-glucuronide (M6G), DAMGO ([d-Ala(2), N-Me-Phe(4), Gly(5)-ol]enkaphalin) and VEGF induced migration which were inhibited by pretreatment with MNTX at therapeutically relevant concentration (0.1 microM). The biologically inactive metabolite morphine-3-glucuronide (M3G) did not affect EC migration. We next examined the mechanism(s) by which MNTX inhibits opioid and VEGF-induced angiogenesis using human pulmonary microvascular EC. MS and DAMGO induced Src activation which was required for VEGF receptor transactivation and opioid-induced EC proliferation and migration. MNTX inhibited MS, DAMGO and VEGF induced tyrosine phosphorylation (transactivation) of VEGF receptors 1 and 2. Furthermore, MS, DAMGO and VEGF induced RhoA activation which was inhibited by MNTX or VEGF receptor tyrosine kinase inhibition. Finally, MNTX or silencing RhoA expression (siRNA) blocked MS, DAMGO and VEGF-induced EC proliferation and migration. Taken together, these results indicate that MNTX inhibits opioid-induced EC proliferation and migration via inhibition of VEGF receptor phosphorylation/transactivation with subsequent inhibition of RhoA activation. These results suggest that MNTX inhibition of angiogenesis can be a useful therapeutic intervention for cancer treatment.
Insights
Methylnaltrexone (MNTX) inhibits cancer angiogenesis by blocking opioid and VEGF-induced endothelial cell proliferation and migration. This suggests MNTX as a potential therapeutic agent for various malignancies.
Area of Science:
- Oncology
- Pharmacology
- Cell Biology
Background:
- Angiogenesis, the formation of new blood vessels, is crucial for tumor growth and metastasis.
- Inhibiting angiogenesis is a key therapeutic strategy for numerous cancers.
- Methylnaltrexone (MNTX) is a peripheral mu opioid receptor antagonist.
Purpose of the Study:
- To investigate the effects of MNTX on agonist-induced human endothelial cell (EC) proliferation and migration.
- To elucidate the mechanisms by which MNTX inhibits opioid and VEGF-induced angiogenesis.
Main Methods:
- Human dermal and pulmonary microvascular ECs were used to assess proliferation and migration.
- Opioid agonists (morphine sulfate, DAMGO) and VEGF were employed to induce angiogenesis-related processes.
- MNTX, Src activation inhibitors, and RhoA silencing (siRNA) were utilized to investigate signaling pathways.
- VEGF receptor phosphorylation and RhoA activation were measured.
Main Results:
- MNTX inhibited morphine sulfate, M6G, DAMGO, and VEGF-induced EC migration.
- Opioid agonists induced Src activation, which was necessary for VEGF receptor transactivation and EC proliferation/migration.
- MNTX blocked opioid and VEGF-induced tyrosine phosphorylation of VEGF receptors 1 and 2.
- MNTX inhibited opioid and VEGF-induced RhoA activation, which was essential for EC proliferation and migration.
Conclusions:
- MNTX inhibits opioid-induced EC proliferation and migration by blocking VEGF receptor phosphorylation/transactivation and subsequent RhoA activation.
- These findings suggest MNTX has potential as a therapeutic intervention for inhibiting cancer angiogenesis.
